Blocking the Thromboxane Receptor Prevents Alzheimer's Disease in Mouse Model

A recent study carried out on a transgenic mouse model of Alzheimer's disease identified the thromboxane receptor (TP) as an active contributor to the development of the disease and a feasible target for drugs to treat it.

Investigators at Temple University (Philadelphia, PA, USA) had reported previously that 8-isoprostaneF2alpha (8ISO)—a marker for lipid oxidation and an indicator of oxidative stress—increased brain amyloid-beta levels and deposition in the Tg2576 mouse Alzheimer's disease model.

In the current study, the investigators continued this line of research by examining how (8ISO) affected behavior and tau protein metabolism. To this end, they characterized the behavioral, biochemical, and neuropathologic effects of 8ISO in the triple transgenic mouse model.

They reported in the October 10, 2014, online edition of the journal Neurobiology of Aging that compared with controls, the transgenic mice receiving 8ISO showed significant memory deficits, increase in tau phosphorylation, activation of the cyclin kinase-5 pathway, and neuroinflammation. All these effects could be prevented by treatment with drugs that blocked the thromboxane receptor, a G-protein coupled receptor coupled to the G protein Gq.

“Besides the two major signature brain pathologies associated with Alzheimer’s disease, amyloid beta plaques and the tangles which are formed from the phosphorylation of the tau protein, researchers have also known for a while that there is a signature from oxidation stress,” said senior author Dr. Domenico Praticò, professor of pharmacology, microbiology, and immunology in Temple University. “But it has always been believed that oxidative stress was just a bystander and did not have an active function in the development of the disease.”

“For the first time we have identified this receptor as the culprit responsible for the bad things that happen with the disease when high levels of oxygen free radicals are produced,” said Dr. Praticò. “Basically, it sends the wrong message inside the neuronal cells, and with time, this definitely will result in all the clinical manifestations of the disease, such as cognitive impairment, loss of memory, and brain cell death. This indirectly confirmed for us that the free radicals worked through this receptor.”

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